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Review
. 2007 Feb:265-266:77-82.
doi: 10.1016/j.mce.2006.12.007. Epub 2007 Jan 16.

Identification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor

Trevor M Penning  1 , David R Bauman, Yi Jin, Tea Lanisik Rizner
Affiliations
Review

Identification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor

Trevor M Penning et al. Mol Cell Endocrinol. 2007 Feb.

Abstract

Pairs of hydroxysteroid dehydrogenases (HSDs) govern ligand access to steroid receptors in target tissues and act as molecular switches. By acting as reductases or oxidases, HSDs convert potent ligands into their cognate inactive metabolites or vice versa. This pre-receptor regulation of steroid hormone action may have profound effects on hormonal response. We have identified the HSDs responsible for regulating ligand access to the androgen receptor (AR) in human prostate. Type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) acts solely as a reductase to convert 5alpha-dihydrotestosterone (DHT), a potent ligand for the AR (K(d)=10(-11)M for the AR), to the inactive androgen 3alpha-androstanediol (K(d)=10(-6)M for the AR); while RoDH like 3alpha-HSD (a short-chain dehydrogenase/reductase (SDR)) acts solely as an oxidase to convert 3alpha-androstanediol back to 5alpha-DHT. Our studies suggest that aldo-keto reductase (AKRs) and SDRs function as reductases and oxidases, respectively, to control ligand access to nuclear receptors.

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Figures

Fig. 1
Fig. 1
Regulation of ligand occupancy of the AR by HSDs in human prostate.
Fig. 2
Fig. 2
AKR1C2 and AKR1C9 preferentially catalyze the reduction of 5α-DHT to 3α-diol in COS-1 cells. Percent conversion of 5α-DHT to 3α-diol in COS-1 cells stably transfected with pcDNA3 (mock), pcDNA3-AKR1C9 (rat 3α-HSD; positive control) or pcDNA3-AKR1C2 (human type 3 3α-HSD). Cells were incubated with 5 μM [14C]-5α-DHT. Adapted from Rizner at al. 2003.
Fig. 3
Fig. 3
RL-HSD preferentially catalyzes the oxidation of 3α-diol to 5α-DHT. Percent conversion of 3α-diol to DHT in COS-1 cells stably transfected with bis-cistronic constructs (pcDNA3-3α-HSDisofrom-LacZ) where the 3α-HSD isoform corresponds to RoDH4 (■); RL-HSD (○); RoDH5 (□); NT-3α-HSD (♦); ERAB (▽) and pcDNA3 (▲). Cells were incubated with 0.1 μM [3H]-3α-diol. Percent conversion was normalized to β-galacosidase activity, and conversion to 5α-DHT and 5α-androstane-3,17-dione were combined due to the endogenous 17β-HSD present. Adapted from Bauman, et al. 2006a.
Fig. 4
Fig. 4
Trans-activation of the AR by 3α-diol in the presence of oxidative 3α-HSDs. (A), Activation of the (ARE)2-tk-CAT reporter gene by the AR in the presence of co-transfected HSDs versus the concentration of 3α-diol (10−12 to 10−6 M); (B) the calculated EC50 values to reach a 100% trans-activation; where 100% trans-activation is the maximal response seen with 5α-DHT. The fold increase in chloramphenicol acetyl transferase (CAT) activity seen at maximal response was 30-fold; and (C) The cellular basis of the assay. Abbreviations, T = testosterone. Adapted from Bauman et al. 2006a.
Fig. 5
Fig. 5
Expression of AKR1C2 and RL-HSD in primary cultures of epithelial and stromal cells taken from normal patients, cancer patients (CaP), and patients with benign prostatic hyperplasia (BPH). Cells were obtained from biopsy samples under an IRB approved protocol obtained by Dr. Donna M. Peehl at the University of Stanford. Cells were cultured as described (Bauman et al, 2006b). AKR1C2 and RL-HSD were quantified by real-time RT-PCR using validated primers (Bauman et al., 2006b) and amounts were normalized to two housekeeping genes (GAPDH-high abundance and porphobilinogen deaminase low abundance) and expressed as fg transcript per ng of total cDNA. The box plots show the median values and their associated standard areas. Adapted from Bauman et al. 2006b.
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